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Despite the availability of target drugs in the first and second line, only 30% of FLT3mut AMLs are cured. Among the multiple mechanisms of resistance, those of FLT3mut LSC are the most difficult to eradicate because of their metabolic and genomic characteristics. Reactivation of glycogen synthesis, inhibition of the RAS/MAPK pathway, and degradation of FLT3 may be potential aids to fight the resistance of LSC to FLT3i. LSC is also characterized by the expression of a CD34+/CD25+/CD123+/CD99+ immunophenotype. The receptor and ligand of FLT3, the natural killer group 2 member D ligand (NKGD2L), and CD123 are some of the targets of chimeric antigen receptor T cells (CAR-T), bispecific T-cell engager molecules (BiTEs), CAR-NK and nanoparticles recently designed and reported here. The combination of these new therapeutic options, hopefully in a minimal residual disease (MRD)-driven approach, could provide the future answer to the challenge of treating FLT3mut AML.

FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30–40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30–50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation.

Amyloid Light Chain (AL) Amyloidosis is a rare disorder of protein misfolding and metabolism characterized by insoluble fibrils deposition in various tissues and organs, which could quickly progress and become fatal. The most frequently affected organ is heart being its involvement the most adverse prognostic feature. Kidney and liver could be other organ localizations, defining AL Amyloidosis as a multisystem disorder. Being Budd-Chiari syndrome (BCS) an uncommon congestive hepatopathy caused by blockage of hepatic veins in the absence of cardiac disorders, it could be rarely caused by a massive deposition of amyloid proteins into hepatic sinusoidal spaces, giving an uncommon clinical presentation of AL Amyloidosis.

The achievement of complete remission (CR) is crucial for acute myeloid leukemia (AML) patients undertaking curative therapy, but relapse often occurs within months, highlighting the need for strategies to prolong disease-free survival (DFS). Our phase III study compared the efficacy and safety of azacitidine (AZA) to best supportive care (BSC) in elderly AML patients who achieved CR following intensive induction and consolidation therapy. This ancillary study (QOL-ONE Trans-2) evaluated biological changes in bone marrow using Next-Generation Sequencing (NGS). We analyzed baseline, randomization, and 6-month post-remission samples from 24 patients (median age of 71 and 12 males). High-throughput NGS targeted 350 myeloid malignancy-related genes, considering variants with a variant allele frequency ≥ 4%. At diagnosis, all patients had 5 to 17 (median = 10) mutations, with DNMT3A (42%), NPM1 (33%), and TET2 (33%) being most frequent. FANCA mutations in four patients were linked to a higher relapse risk (HR = 4.96, p = 0.02) for DFS at both 2 and 5 years. Further HLA-specific NGS analyses are ongoing to confirm these results and their therapeutic implications.

Initial evidence of CPX-351 activity in patients younger than 60 years emerged from a phase I trial [1]; however, subsequent pivotal phase III trial focused on older patients (≥60 years), where CPX-351 demonstrated superiority over conventional ‘7 + 3’ induction, in in secondary acute myeloid leukemia (sAML), including therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC), showing higher overall response rates (ORR), improved overall survival (OS) and increased haematopoetic stem cell transplantation (HSCT) rate [2]. Since CPX-351 is approved for all adult sAML, we conducted a multicentric retrospective study in patients <60. No differences in event-free survival (EFS) were observed according to clinical and laboratory parameters (Supplementary Table S10). [...]those transplanted with active disease had poor outcomes, with mOS of 9.6 months.In the landmark analysis, patients transplanted in first CR had not reached mOS, while no significant OS differences were observed by CK presence (Fig. 2C). The UK NCRI AML19 trial further compared CPX-351 with FLAG-Ida in younger adults with high-risk AML/MDS, showing no OS difference but improved RFS with CPX-351, particularly in patients with MDS-related gene mutations [12].

This phase-3 randomized multicenter trial evaluated the efficacy of subcutaneous azacitidine (AZA) post-remission therapy vs. best supportive care (BSC) in elderly acute myeloid leukemia (AML) patients. The primary endpoint was the difference in disease-free survival (DFS) from complete remission (CR) to relapse/death. Patients with newly diagnosed AML aged ≥61 years received two courses of induction chemotherapy (“3+7” daunorubicin and cytarabine) followed by consolidation (cytarabine). At CR, 54 patients were randomized (1:1) to receive BSC (N = 27) or AZA (N = 27) at a dose of 50 mg/m2 for 7 days every 28 days and the dose increased after the 1st cycle to 75 mg/m2 for a further 5 cycles, followed by cycles every 56 days for 4.5 years. At 2 years, median DFS was 6.0 (95% CI: 0.2–11.7) months for patients receiving BSC vs. 10.8 months (95% CI: 1.9–19.6, p = 0.20) months for AZA. At 5 years, DFS was 6.0 (95% CI: 0.2–11.7) months in the BSC arm vs. 10.8 (95% CI: 1.9–19.6, p = 0.23) months in the AZA arm. Significant benefit was afforded by AZA on DFS at 2 and 5 years in patients aged >68 years (HR = 0.34, 95% CI: 0.13–0.90, p = 0.030 and HR = 0.37, 95% CI: 0.15–0.93, p = 0.034, respectively). No deaths occurred prior to leukemic relapse. Neutropenia was the most frequent adverse event. There were no differences in patient-reported outcome measures between study arms. In conclusion, AZA post-remission therapy was found to provide benefit in AML patients aged >68 years.

Surveillance of Echinococcus multilocularis at the edge of its range is hindered by fragmented distributional patterns and low prevalence in definitive hosts. Thus, tests with adequate levels of sensitivity are especially important for discriminating between infected and non-infected areas. In this study we reassessed the prevalence of E . multilocularis at the southern border of its distribution in Province of Bolzano (Alto Adige, northeastern Alps, Italy), to improve surveillance in wildlife and provide more accurate estimates of exposure risk. We compared the diagnostic test currently implemented for surveillance based on coproscopy and multiplex PCR (CMPCR) to a real-time quantitative PCR (qPCR) in 235 fox faeces collected in 2019 and 2020. The performances of the two tests were estimated using a scraping technique (SFCT) applied to the small intestines of a subsample (n = 123) of the same foxes as the reference standard. True prevalence was calculated and the sample size required by each faecal test for the detection of the parasite was then estimated. True prevalence of E . multilocularis in foxes (14.3%) was markedly higher than reported in the last decade, which was never more than 5% from 2012 to 2018 in the same area. In addition, qPCR showed a much higher sensitivity (83%) compared to CMPCR (21%) and agreement with the reference standard was far higher for qPCR (0.816) than CMPCR (0.298) meaning that for the latter protocol, a smaller sample size would be required to detect the disease. Alto Adige should be considered a highly endemic area. Routine surveillance on definitive hosts at the edges of the E . multilocularis distribution should be applied to smaller geographic areas, and rapid, sensitive diagnostic tools using directly host faeces, such as qPCR, should be adopted.

Background Echinococcus multilocularis is a small tapeworm affecting wild and domestic carnivores and voles in a typical prey-predator life cycle. In Italy, there has been a focus of E. multilocularis since 1997 in the northern Italian Alps, later confirmed in red foxes collected from 2001 to 2005. In this study, we report the results of seven years of monitoring on E. multilocularis and other cestodes in foxes and describe the changes that occurred over time and among areas (eco-regions) showing different environmental and ecological features on a large scale. Methods Eggs of cestodes were isolated from feces of 2872 foxes with a sedimentation/filtration technique. The cestode species was determined through multiplex PCR, targeting and sequencing ND1 and 12S genes. Analyses were aimed to highlight variations among different eco-regions and trends in prevalence across the study years. Results Out of 2872 foxes, 217 (7.55%) samples resulted positive for cestode eggs at coproscopy, with differences of prevalence according to year, sampling area and age class. Eight species of cestodes were identified, with Taenia crassiceps (2.65%), Taenia polyacantha (1.98%) and E. multilocularis (1.04%) as the most represented. The other species, Mesocestoides litteratus, Taenia krabbei, T. serialis, T. taeniaeformis and Dipylidium caninum , accounted for < 1% altogether. Echinococcus multilocularis was identified in foxes from two out of six eco-regions, in 30 fecal samples, accounting for 1.04% within the cestode positives at coproscopy. All E. multilocularis isolates came from Bolzano province. Prevalence of cestodes, both collectively and for each of the three most represented species ( T. crassiceps, T. polyacantha and E. multilocularis ), varied based on the sampling year, and for E. multilocularis an apparent increasing trend across the last few years was evidenced. Conclusions Our study confirms the presence of a focus of E. multilocularis in red foxes of northeast Italy. Although this focus seems still spatially limited, given its persistence and apparent increasing prevalence through the years, we recommend research to be conducted in the future on the ecological factors that, on a smaller scale, allow this zoonotic species to persist. On the same scale, we recommend a health education campaign to inform on the measures to prevent this zoonosis, targeted at people living in the area, especially hunters, dog owners, forestry workers and other potentially exposed categories.

Surveillance of Echinococcus multilocularis at the edge of its range is hindered by fragmented distributional patterns and low prevalence in definitive hosts. Thus, tests with adequate levels of sensitivity are especially important for discriminating between infected and non-infected areas. In this study we reassessed the prevalence of E. multilocularis at the southern border of its distribution in Province of Bolzano (Alto Adige, northeastern Alps, Italy), to improve surveillance in wildlife and provide more accurate estimates of exposure risk. We compared the diagnostic test currently implemented for surveillance based on coproscopy and multiplex PCR (CMPCR) to a real-time quantitative PCR (qPCR) in 235 fox faeces collected in 2019 and 2020. The performances of the two tests were estimated using a scraping technique (SFCT) applied to the small intestines of a subsample (n = 123) of the same foxes as the reference standard. True prevalence was calculated and the sample size required by each faecal test for the detection of the parasite was then estimated. True prevalence of E. multilocularis in foxes (14.3%) was markedly higher than reported in the last decade, which was never more than 5% from 2012 to 2018 in the same area. In addition, qPCR showed a much higher sensitivity (83%) compared to CMPCR (21%) and agreement with the reference standard was far higher for qPCR (0.816) than CMPCR (0.298) meaning that for the latter protocol, a smaller sample size would be required to detect the disease. Alto Adige should be considered a highly endemic area. Routine surveillance on definitive hosts at the edges of the E. multilocularis distribution should be applied to smaller geographic areas, and rapid, sensitive diagnostic tools using directly host faeces, such as qPCR, should be adopted.